d-Sotalol may be a clinically useful class III antiarrhythmic agent for controlling ventricular arrhythmias in children. Because age-related differences in repolarization currents may contribute to developmental differences in response to antiarrhythmic agents that primarily affect repolarization, the electrophysiologic effects of d-sotalol were compared in Purkinje fibers from neonatal and adult dogs. Significant age-related changes characterized the antiarrhythmic profile of d-sotalol. d-Sotalol (10-4M) significantly prolonged the action potential duration of adult Purkinje fibers (310 ≤ 8 to 380 ≤ 7 ms, p < 0.01) and neonatal fibers (247 ≤ 5 to 342 ≤ 9 ms, p < 0.01). However, the lengthening of action potential duration was significantly greater in the immature age group. d-Sotalol had no significant effect on maximum diastolic potential, action potential amplitude, or phase zero upstroke velocity in normally polarized fibers. In contrast, different electrophysiologic effects were observed in K+-depolarized Purkinje fibers. Superfusion of adult K+-depolarized fibers with d-sotalol suppressed excitability in five (38%) of 13 fibers and significantly decreased action potential amplitude (88 ≤ 2 to 83 ≤ 1 mV, p < 0.05) and phase zero upstroke velocity (180 ≤ 14 to 105 ≤ 3 V/s, p < 0.01) in the other eight fibers. The membrane depressant effects observed in the younger age group were significantly less (no suppression of excitability and a smaller decrease in phase zero upstroke velocity (121 ≤ 22 to 101 ≤ 23 V/s, p < 0.05). The magnitude of action potential duration prolongation by d-sotalol in K+-depolarized fibers was less than in normally polarized fibers. These results suggest that at the clinical level the mechanism of d-sotalol's antiarrhythmic action will depend not only on the developmental maturity, but also on the resting membrane potential of the tissue treated.